Abstract
A large body of work has established the prominent roles of the atrial M2R-IKACh signaling pathway, and the negative regulatory protein RGS6, in modulating critical aspects of parasympathetic influence on cardiac function, including pace-making, heart rate (HR) variability (HRV), and atrial arrhythmogenesis. Despite increasing evidence of its innervation of the ventricles, and the expression of M2R, IKACh channel subunits, and RGS6 in ventricle, the effects of parasympathetic modulation on ventricular electrophysiology are less clear. The main objective of our study was to investigate the contribution of M2R-IKACh signaling pathway elements in murine ventricular electrophysiology, using in-vivo ECG measurements, isolated whole-heart optical mapping and constitutive knockout mice lacking IKACh (Girk4–/–) or RGS6 (Rgs6-/-). Consistent with previous findings, mice lacking GIRK4 exhibited diminished HR and HRV responses to the cholinergic agonist carbachol (CCh), and resistance to CCh-induced arrhythmic episodes. In line with its role as a negative regulator of atrial M2R-IKACh signaling, loss of RGS6 correlated with a mild resting bradycardia, enhanced HR and HRV responses to CCh, and increased propensity for arrhythmic episodes. Interestingly, ventricles from mice lacking GIRK4 or RGS6 both exhibited increased action potential duration (APD) at baseline, and APD was prolonged by CCh across all genotypes. Similarly, CCh significantly increased the slope of APD restitution in all genotypes. There was no impact of genotype or CCh on either conduction velocity or heterogeneity. Our data suggests that altered parasympathetic signaling through the M2R-IKACh pathway can affect ventricular electrophysiological properties distinct from its influence on atrial physiology.
Highlights
The autonomic nervous system (ANS) plays an important role in regulating cardiac electrical activity
To confirm the impact of M2R-IKACh signaling on atrial physiology, heart rate (HR) and HR variability (HRV) was assessed in WT, Girk4–/, and Rgs6–/–mice at baseline and after CCh injection using in-vivo ECG recordings from anesthetized mice
Injection of CCh evoked a significant decrease in HR for both WT and Rgs6-/- mice, whereas no significant change in HR was seen for Girk4-/- mice (Fig 1A)
Summary
The autonomic nervous system (ANS) plays an important role in regulating cardiac electrical activity Both branches of the ANS, namely the sympathetic and parasympathetic systems, directly innervate the heart and influence cardiac electrophysiology. In sinoatrial nodal cells and atrial myocytes, the activation of M2R triggers the release of inhibitory G proteins, which proceed to modulate the activity of multiple downstream targets. Among these is the activation of the G protein-gated inwardly rectifying K+ channel IKACh, a heterotetrameric complex formed by GIRK1 and GIRK4 subunits which exerts a prominent effect on both HR and HR variability (HRV) [5, 6]. Loss of RGS6 in mice results in an increase in IKACh activity which, in contrast to Girk4–/–mice, correlates with an increase in CCh induced bradycardia, increase in HRV, and increase in susceptibility to pacing induced AF [8,9,10]
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